I’ve previously talked about the common misconception that viruses evolve toward benignity. This is usually phrased something like, “Natural selection favours viruses with low pathogenicity/virulence (so they don’t eradicate their hosts)“, or “Viral pathogenesis is an abnormal situation of no value to the virus“. This claim is clearly wrong — “clearly” both through common sense, and through observation.

Common sense tells us that pathogenicity does benefit at least some viruses. If a virus is spread through fecal/oral contamination (like noroviruses, say), then increasing fecal production will increase viral spread; we perceive that as diarrhea, fluid loss, illness and perhaps death — pathogenicity. In this case, the virus obviously benefits from virulence; there’s no pressure on the virus to evolve toward reduced pathogenicity, because that would reduce its transmission.

I talked about this with myxomavirus — one of the few well-studied cases where the concept can actually be tested. Myxoma was introduced to Australia in the early 1950s as a biological control agent for the rabbit plague. At first, the virus killed virtually every rabbit it infected (99.8% lethality), reducing the rabbit population by 85%, to a mere 100,000,000; but after some years of adaptation, most rabbits survived infection, and the rabbit population rebounded. However, the virus did not evolve to “low pathogenicity”; rather it evolved to a point where it killed about 70% of rabbits it infected. (To put that in context, it’s the same ballpark as smallpox, or Ebola — viruses which are not usually considered to have low virulence.) In this case, the reduced (but still very high) pathogenicity correlated with a longer period of transmission; the rabbits were sick for weeks, and less able to fend off the mosquitos and fleas that spread the virus. The most virulent virus killed the rabbits so fast that not many mosquitos got a chance to bite them. Hence, evolution to reduced, but still very severe, virulence.

But there’s another side of the equation. The host would, very obviously, benefit from reduced viral pathogenicity. This is something that’s hard to separate in natural experiments. When we see, for example, deer mice surviving with minimal disease while infected with Sin Nombre virus, how can we tell if the virus has adapted to the host, the host to the virus, or both?

In this natural myxomavirus experiment, we can in fact address that question, because Australian rabbits had to deal with the virus while their European cousins didn’t. And as you’d expect, Australian rabbits are actually relatively resistant to myxomavirus.

Below are data from Fenner1 showing survival of wild Australian rabbits when exposed to the same strain of myxomavirus (click for a larger version). (Because the virus was deliberately introduced, it was known what the original strain was, and new strains with defined virulence in European rabbits could be isolated and saved.) The Y axis is the percent of rabbits responding with a certain level of disease; the X axis shows the number of epidemics that had spread through the country before sampling the rabbits.

In the first couple epidemics rabbits were almost all severely infected; but after selection by two or three epidemics, many of the rabbits are only moderately affected by the same strain of virus that killed almost all of their ancestors, and after six or seven epizootics, most rabbits survived and many were only mildly sick:

The belief that evolution is a slow process, undetectable by our mayfly eyes, is long obsolete. Here’s one example of how fast changes can become fixed in a population. As Fenner said:

it was then thought that it might be decades before resistance became evident, and that challenge with something less than fully virulent virus would make it easier to observe the first changes. To our surprise, within a few years, in a population of’ rabbits that had been exposed annually to myxomatosis, the case fatality rate fell from about 90% to about 50%, and eventually even lower than that.

But it’s not so simple. For example, why did it take a few epidemics before resistance arose in the rabbits?

Probably the reduced viral virulence played an important part in that. With a 99.8% mortality, there’s not much room for resistance to arise. After the virus settled down and spared 30% of its hosts, there was room for survivors to pass on their resistance genes. But there are limits:

… the rate of acquisition of resistance had reached a plateau after about six generations of selection (W. R. Sobey, personal communication, 1982). Perhaps this represents a limit to what can be achieved by selection of the pre-existing genotypes; any further change may require the occurrence and selection of mutations for resistance.

(That was written in 1983, and I don’t actually know if resistance has progressed further.)

We don’t know (or at least I don’t know; and I haven’t seen anything published on it) exactly what the resistance factors are in the resistant rabbits. However, it’s interesting that apparently a major cause of myxomavirus disease is “an acute and overwhelming immunopathological response to the virus“,2 because this brings me back to the deer mouse/hantavirus story I mentioned earlier. It seems that mice respond to Sin Nombre virus with a regulatory T cell response — dampening immune responses rather than enhancing them — and this may be one reason they don’t show disease (i.e. they’ve removed the immunopathological side of the equation). I wonder if Australian rabbits have also evolved a tendency to develop TReg responses to myxoma virus.

In any case I can’t offer a better summary than Fenner’s:

Observations of its effects after some 30 years show that a fantastically virulent virus did not eradicate the rabbit, but that selection for transmissibility, especially during the off-season (winter in Australia) allowed the early emergence and rapid dominance of strains of lowered virulence. We now see a fascinating interplay between genetic changes in host and virus.

Fenner F. Biological control, as exemplified by smallpox eradication and myxomatosis. Proceeding of the Royal Society of London, Series B, The Florey Lecture, 1983: Biological Control, as Exemplified by Smallpox Eradication and Myxomatosis 1983;218:259-285.[↩]

Yeah, but that’s kind of my point: You simply can’t blithely extrapolate from one virus and make claims for another, no matter how closely-related it may seem. Smallpox/cowpox, HIV/SIV, Poliovirus/rhinovirus … you have to actually look at the reality.

[…] of about 12%, which is still extremely lethal. That said, trends in viral evolution tend towards decreased pathogenicity over time; it’s more beneficial to the virus to keep the host alive, as more viral particles […]

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